Extending in vim half-life of therapeutic proteins, thereby enhancing their efficiency is a major concern in the pharmaceutical field. Numerous strategies have been employed towards this end, including covalent modification, such as through PEGylation or Fc-Fusion proteins, which improves protein stability and solubility, prevents proteolytic degradation, and reduces the clearance rate from the bloodstream. Such approaches have been applied to different therapeutic proteins and for different disorders such as Haemophilia A which is a bleeding disorder caused by defects in the gene encoding coagulation factor VIII (FVIII) and affects 1-2 in 10,000 male births. Patients affected with hemophilia A can be treated with infusion of purified plasma-derived or recombinantly produced FVIII. All commercially available FVIII products, however, are known to have a short half-life of several hours (7-21 hours. Van Dijk et al Haematologica 2005 92:494-498), requiring frequent intravenous administration to the patients. Thus, a number of approaches have been tried in order to extend the FVIII half-life. For example, the approaches in development to extend the half-life of clotting factors include chemical (PEGylation)1 or genetic modification (Fc-fusion)2 of the FVIII molecule. Regardless of the protein engineering used, however, the long acting FVIII products currently under development are repotted to have limited half-lives—only to about 1-5 to 2 hours in preclinical animal models. Consistent results have been demonstrated in humans, for example, rFVIIIFc was reported to improve half-life up to 1.7 fold compared with ADVATE® in hemophilia A patients.
Due to the frequent dosing and inconvenience caused by the dosing schedule, there is still a need to develop FVIII products requiring less frequent administration, i.e., a FVIII product that has a half-life longer than the 1.5 to 2 fold half-life limitation.